Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel

Chao Liu; Wei Liu; Yanhong Liu; Hongxia Duan; Liqing Chen; Xintong Zhang; Mingji Jin; Minhu Cui; Xiuquan Quan; Libin Pan; Jiachun Hu; Zhonggao Gao; Yan Wang; Wei Huang

doi:10.1016/j.apsb.2023.05.029

Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel

Acta Pharm Sin B. 2023 Aug;13(8):3425-3443. doi: 10.1016/j.apsb.2023.05.029. Epub 2023 May 26.

Authors

Chao Liu^{1

2}, Wei Liu^{1

3}, Yanhong Liu^{1

2}, Hongxia Duan^{1

2}, Liqing Chen^{1

2}, Xintong Zhang^{1

2}, Mingji Jin^{1

2}, Minhu Cui⁴, Xiuquan Quan⁴, Libin Pan¹, Jiachun Hu¹, Zhonggao Gao^{1

2}, Yan Wang¹, Wei Huang^{1

2}

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
² Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
³ Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Brain and Intelligence Research Key Laboratory of Chongqing Education Commission, Third Military Medical University, Chongqing 400038, China.
⁴ Department of Gastroenterology, Yanbian University Hospital, Yanji 133000, China.

Abstract

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Keywords: Bile acids; Bioavailability; Chemotherapy; Intestine epithelium targeting; Mucus penetration; Oral nanoparticles; Paclitaxel; Trans-epithelium.